Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ.

All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARß, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.

Structure and the Anticancer Activity of Vitamin D Receptor Agonists.

Vitamin D is a group of seco-steroidal fat-soluble compounds. The two basic forms, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol), do not have biological activity. They are converted in the body by a two-step enzymatic hydroxylation into biologically active forms, 1α,25-dihydroxyvitamin D2 [ercalcitriol, 1,25(OH)2D2] and 1α,25-dihydroxyvitamin D3 [calcitriol, 1,25(OH)2D3], which act as classical steroid hormones. 1,25(OH)2D3 exerts most of its physiological functions by binding to the nuclear vitamin D receptor (VDR), which is present in most body tissues to provide support to a broad range of physiological processes. Vitamin D-liganded VDR controls the expression of many genes. High levels of 1,25(OH)2D3 cause an increase in calcium in the blood, which can lead to harmful hypercalcemia. Several analogs of 1,25(OH)2D3 and 1,25(OH)2D2 have been designed and synthesized with the aim of developing compounds that have a specific therapeutic function, for example, with potent anticancer activity and a reduced toxic calcemic effect. Particular structural modifications to vitamin D analogs have led to increased anticancer activity and reduced calcemic action with the prospect of extending work to provide future innovative therapies.

Vitamin D and immune system.

The active metabolite of vitamin D 1,25(OH)2D is well known for its role in regulating calcium-phosphate homeostasis of the human body. However, the immunomodulating activity of 1,25(OH)2D has been known for many years. There are numerous reports correlating low vitamin D levels in blood serum with the onset of autoimmune diseases and with the severe course of acute infections. In this chapter, we address the role of 1,25(OH)2D in these diseases, and we discuss the possible mechanisms of action of 1,25(OH)2D in immune cells.

Life Stress and Unmarried, Black Fathers' Attitudes Toward Attachment: The Moderating Role of Shift-and-Persist.

Unmarried, Black fathers' positive engagement contributes to children's health and development beginning in early infancy. For many men, preparations for parenthood begin before birth as expectant fathers formulate parenting attitudes that can promote secure infant-father attachment relationships. This study examined aspects of life stress as predictors of prenatal attitudes toward attachment -- the extent to which expectant fathers endorsed promoting attachment security in their infants. Further, we considered whether shift-and-persist cognitive strategies -- a psychological resilience factor focused on shifting to positive focus and future-orientation -- moderated these associations. A sample of 121 unmarried, Black men expecting the birth of a child were recruited during the 2nd or 3rd trimester of their partner's pregnancy. Expectant fathers reported on childhood trauma, recent negative life experiences, and depressive symptomology. Fathers also completed a survey assessment of shift-and-persist strategies, as well as a newly developed scale assessing attitudes toward attachment. Depressive symptoms and negative life events were directly, positively related to attitudes toward attachment. The association between positive attitudes toward attachment and both negative life events and depressive symptomology was moderated by fathers' ability to shift-and-persist. Specifically, aspects of life stress were generally unrelated to attitudes toward attachment when shift-and-persist was low, but related to more positive attitudes toward attachment when shift-and-persist was high. Preliminary findings point to the potential steeling effects of shift-and-persist strategies for expectant fathers facing moderate levels of life stress.

Attachment relationship quality with mothers and fathers and child temperament: An individual participant data meta-analysis.

A growing body of research suggests that, compared with single parent-child attachment relationships, child developmental outcomes may be better understood by examining the configurations of child-mother and child-father attachment relationships (i.e., attachment networks). Moreover, some studies have demonstrated an above-chance level chance of concordance between the quality of child-mother and child-father attachment relationships, and child temperament has been offered as a plausible explanation for such concordance. To assess whether temperament plays a role in the development of different attachment network configurations, in this preregistered individual participant data meta-analysis we tested the degree to which the temperament dimension of negative emotionality predicts the number of secure, insecure-avoidant, insecure-resistant, and disorganized attachment relationships a child has with mother and father. Data included in the linear mixed effects analyses were collected from seven studies sampling 872 children (49% female; 83% White). Negative emotionality significantly predicted the number of secure (d = -0.12) and insecure-resistant (d = 0.11), but not insecure-avoidant (d = 0.04) or disorganized (d = 0.08) attachment relationships. Nonpreregistered exploratory analyses indicated higher negative emotionality in children with insecure-resistant attachment relationships with both parents compared to those with one or none (d = 0.19), suggesting that temperament plays a small yet significant role in child-mother/child-father insecure-resistant attachment relationships concordance. Taken together, results from this study prompt a more in-depth examination of the mechanism underlying the small yet significantly higher chance that children with increased negative emotionality have for developing multiple insecure-resistant attachment relationships. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Configurations of mother-child and father-child attachment relationships as predictors of child language competence: An individual participant data meta-analysis.

An individual participant data meta-analysis was conducted to test pre-registered hypotheses about how the configuration of attachment relationships to mothers and fathers predicts children's language competence. Data from seven studies (published between 1985 and 2014) including 719 children (Mage : 19.84 months; 51% female; 87% White) were included in the linear mixed effects analyses. Mean language competence scores exceeded the population average across children with different attachment configurations. Children with two secure attachment relationships had higher language competence scores compared to those with one or no secure attachment relationships (d = .26). Children with two organized attachment relationships had higher language competence scores compared to those with one organized attachment relationship (d = .23), and this difference was observed in older versus younger children in exploratory analyses. Mother-child and father-child attachment quality did not differentially predict language competence, supporting the comparable importance of attachment to both parents in predicting developmental outcomes.

Deregulation of All-Trans Retinoic Acid Signaling and Development in Cancer.

Cancer stem cells are the root cause of cancer, which, in essence, is a developmental disorder. All-trans retinoic acid (ATRA) signaling via ligand-activation of the retinoic acid receptors (RARs) plays a crucial role in tissue patterning and development during mammalian embryogenesis. In adults, active RARγ maintains the pool of hematopoietic stem cells, whereas active RARα drives myeloid cell differentiation. Various findings have revealed that ATRA signaling is deregulated in many cancers. The enzymes for ATRA synthesis are downregulated in colorectal, gastric, lung, and oropharyngeal cancers. ATRA levels within breast, ovarian, pancreatic, prostate, and renal cancer cells were lower than within their normal counterpart cells. The importance is that 0.24 nM ATRA activates RARγ (for stem cell stemness), whereas 100 times more is required to activate RARα (for differentiation). Moreover, RARγ is an oncogene regarding overexpression within colorectal, cholangiocarcinoma, hepatocellular, ovarian, pancreatic, and renal cancer cells. The microRNA (miR) 30a-5p downregulates expression of RARγ, and miR-30a/miR-30a-5p is a tumor suppressor for breast, colorectal, gastric, hepatocellular, lung, oropharyngeal, ovarian, pancreatic, prostate, and renal cancer. These complementary findings support the view that perturbations to ATRA signaling play a role in driving the abnormal behavior of cancer stem cells. Targeting ATRA synthesis and RARγ has provided promising approaches to eliminating cancer stem cells because such agents have been shown to drive cell death.

Editorial: Special Issue "Stem Cell Biology and Cancer".

Cancer stem cells (CSCs) are now well-established as key players in tumor initiation, progression, and therapy resistance [...].

The safety of lookalikes: a new THC beverage enhancer and a non-THC counterpart.

A new tetrahydrocannabinol (THC) beverage enhancer is available to medical and recreational cannabis consumers across the US. Beverage enhancers that do not contain THC, but instead contain flavored concentrates and/or other additives such as caffeine, are used by squirting the contents of a bottle into water, or other beverage of choice, ad libitum and can be used in a titratable manner according to the user's preference or taste. The THC beverage enhancer described herein has an important safety feature: a mechanism that allows users to measure out a 5-mg dose of THC before they add it to their beverage. This mechanism, however, can be easily bypassed if a user attempts to use the product exactly the same way that its non-THC counterparts are used, by turning the bottle upside down and squirting the contents of the bottle into a beverage ad libitum. The THC beverage enhancer described herein would benefit from additional safety features such as a mechanism that prevents the contents of the bottle from leaving the device when turned upside down and a THC warning label.

Retinoic acid receptor regulation of decision-making for cell differentiation.

All-trans retinoic acid (ATRA) activation of retinoic acid receptors (RARs) is crucial to an organism's proper development as established by findings for mouse foetuses from dams fed a vitamin A-deficient diet. ATRA influences decision-making by embryonic stem (ES) cells for differentiation including lineage fate. From studies of knockout mice, RARα and RARγ regulate haematopoiesis whereby active RARα modulates the frequency of decision-making for myeloid differentiation, but is not essential for myelopoiesis, and active RARγ supports stem cell self-renewal and maintenance. From studies of zebrafish embryo development, active RARγ plays a negative role in stem cell decision-making for differentiation whereby, in the absence of exogenous ATRA, selective agonism of RARγ disrupted stem cell decision-making for differentiation patterning for development. From transactivation studies, 0.24 nM ATRA transactivated RARγ and 19.3 nM (80-fold more) was needed to transactivate RARα. Therefore, the dose of ATRA that cells are exposed to in vivo, from gradients created by cells that synthesize and metabolize, is important to RARγ versus RARα and RARγ activation and balancing of the involvements in modulating stem cell maintenance versus decision-making for differentiation. RARγ activation favours stemness whereas concomitant or temporal activation of RARγ and RARα favours differentiation. Crosstalk with signalling events that are provoked by membrane receptors is also important.

Optimism persists when walking in unpredictable environments.

Humans continuously modulate their control strategies during walking based on their ability to anticipate disturbances. However, how people adapt and use motor plans to create stable walking in unpredictable environments is not well understood. Our purpose was to investigate how people adapt motor plans when walking in a novel and unpredictable environment. We evaluated the whole-body center of mass (COM) trajectory of participants as they performed repetitions of a discrete goal-directed walking task during which a laterally-directed force field was applied to the COM. The force field was proportional in magnitude to forward walking velocity and randomly directed towards either the right or left each trial. We hypothesized that people would adapt a control strategy to reduce the COM lateral deviations created by the unpredictable force field. In support of our hypothesis, we found that with practice the magnitude of COM lateral deviation was reduced by 28% (force field left) and 44% (force field right). Participants adapted two distinct unilateral strategies, implemented regardless of if the force field was applied to the right or to the left, that collectively created a bilateral resistance to the unpredictable force field. These strategies included an anticipatory postural adjustment to resist against forces applied to the left, and a more lateral first step to resist against forces applied to the right. In addition, during catch trials when the force field was unexpectedly removed, participants exhibited trajectories similar to baseline trials. These findings were consistent with an impedance control strategy that provides a robust resistance to unpredictable perturbations. However, we also found evidence that participants made predictive adaptations in response to their immediate experience that persisted for three trials. Due to the unpredictable nature of the force field, this predictive strategy would sometimes result in greater lateral deviations when the prediction was incorrect. The presence of these competing control strategies may have long term benefits by allowing the nervous system to identify the best overall control strategy to use in a novel environment.

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume II.

The highly successful previous Volume 1 [...].

Radiolytic degradation of dodecane substituted with common energetic functional groups.

Explosives exist in and are expected to withstand a variety of harsh environments up to and including ionizing radiation, though little is known about the chemical consequences of exposing explosives to an ionizing radiation field. This study focused on the radiation-induced chemical changes to a variety of common energetic functional groups by utilizing a consistent molecular backbone. Dodecane was substituted with azide, nitro, nitrate ester, and nitramine functional groups and γ-irradiated with 60Co in order to study how the functional group degraded along with what the relative stability to ionizing radiation was. Chemical changes were assessed using a combination of analysis techniques including: nuclear magnetic resonance (NMR) spectroscopy, gas chromatography of both the condensed and gas phases, Raman spectroscopy, and Fourier transform infrared (FTIR) spectroscopy. Results revealed that much of the damage to the molecules was on the energetic functional group and often concentrated on the trigger linkage, also known as the weakest bond in the molecule. The general trend from most to least susceptible to radiolytic damage was found to be D-ONO2 → D-N3 → D-NHNO2 → D-NO2. These results also appear to be in line with the relative stability of these functional groups to things such as photolysis, thermolysis, and explosive insults.

A preliminary evaluation of N-acetylcysteine's effects on patient adherence to treatment for cocaine use disorder.

Introduction: Cocaine use disorder (CUD) is a disabling disease associated with high rates of relapse and intense cravings. Patients with CUD struggle to adhere to treatment, which contributes to relapse and frequent readmissions to residential rehab (RR) facilities. Preliminary studies suggest that N-acetylcysteine (NAC) attenuates cocaine-induced neuroplasticity and, therefore, may assist with cocaine abstinence and adherence to treatment. Methods: This retrospective cohort study obtained data from 20 RR facilities across Western New York. Eligible subjects were 18 or older, diagnosed with CUD, and were divided based on their exposure to 1200 mg NAC twice daily during RR. The primary outcome was treatment adherence measured by outpatient treatment attendance rates (OTA). Secondary outcomes included length of stay (LOS) in RR and craving severity on a 1 to 100 visual analog scale. Results: One hundred eighty-eight (N = 188) patients were included in this investigation: NAC, n = 90; control, n = 98. NAC did not significantly impact OTA (% appointments attended), NAC 68%; control 69%, (P = .89) or craving severity NAC 34 ± 26; control 30 ± 27, (P = .38). Subjects treated with NAC had a significantly longer average LOS in RR compared with controls, NAC 86 ± 30; control 78 ± 26, (P = .04). Discussion: In this study, NAC did not impact treatment adherence but was associated with a significantly longer LOS in RR for patients with CUD. Owing to limitations, these results may not be applicable to the general population. More rigorous studies examining NAC's impact on treatment adherence in CUD are warranted.

Targeting the Retinoic Acid Pathway to Eradicate Cancer Stem Cells.

All-trans retinoic acid is a morphogen during embryogenesis and a teratogen. Cancer is an error of development, and the retinoic acid receptors (RAR) for all-trans retinoic acid play a role in cancer. Expression of the cytosolic aldehyde dehydrogenases, which mediate the last step to the synthesis of all-trans retinoic acid, is deregulated in various human cancers. Inhibiting these enzymes using a variety of agents reduced the proliferation of lung cancer cells, reduced the proliferation and induced apoptosis of ovarian, prostate, squamous, and uterine cancer cells, and sensitised breast, colorectal and ovarian cancer cells to chemotherapeutic agents. RARγ is an oncogene within some cases of AML, cholangiocarcinoma, colorectal cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, prostate cancer, and ovarian cancer. Pan-RAR and RARγ antagonist inhibition of the action of RARγ led to necroptosis of human prostate and pediatric brain tumour cancer stem cells. Treatment of hepatocellular carcinoma cells with the flavenoid acacetin, which interferes with the action of RARγ, decreased cell growth and induced apoptosis. Targeting the retinoic acid pathway is promising regarding the development of new drugs to eradicate cancer stem cells.

Effect of di(n-butyl) phthalate on the blood-testis barrier during puberty onset.

Di(n-butyl) phthalate (DBP) is considered a substance of serious concern because of its reproductive toxicity and endocrine-disrupting properties. Exposure to DBP causes morphological and functional changes in the male reproductive system of birds and mammals. However, there are no detailed reports on the effects of DBP on the Sertoli cell and junctional complexes of the blood-testis barrier (BTB) in birds. The present study investigated dose-related ultrastructural changes in Sertoli cells and junctional complexes of the BTB in adult Japanese quail (Coturnix coturnix japonica) exposed to DBP prior to puberty. A total of 25 Japanese quail were used for the study. Exposure to DBP doses of 50, 200 and 400 mg DBP/kg/d caused dose-related ultrastructural changes in junctional complexes including dilation and separation, while disruption of cytoplasmic membranes and mitochondria was observed in Sertoli cells. There was a significant difference in the sum of vacuoles, vacuole diameter, nuclear width, nuclear length, nuclear area, sum of damaged spherical mitochondria, width of elongated mitochondria and the sum of damaged elongated mitochondria among the five treatment groups (p Ë‚ 0.05). Prepubertal exposure to DBP at doses of 50, 200 and 400 mg DBP/kg/d for 30 days led to adverse effects in the adult male Japanese quail reproductive system by inducing structural changes in the Sertoli cells and junctional complexes. Such changes might disrupt the BTB and potentially interfere with spermatogenesis. Results indicated that the Sertoli cell is sensitive to DBP exposure and might be an important cellular target for DBP-induced testicular toxicity.

Chemical Descriptors for a Large-Scale Study on Drop-Weight Impact Sensitivity of High Explosives.

The drop-weight impact test is an experiment that has been used for nearly 80 years to evaluate handling sensitivity of high explosives. Although the results of this test are known to have large statistical uncertainties, it is one of the most common tests due to its accessibility and modest material requirements. In this paper, we compile a large data set of drop-weight impact sensitivity test results (mainly performed at Los Alamos National Laboratory), along with a compendium of molecular and chemical descriptors for the explosives under test. These data consist of over 500 unique explosives, over 1000 repeat tests, and over 100 descriptors, for a total of about 1500 observations. We use random forest methods to estimate a model of explosive handling sensitivity as a function of chemical and molecular properties of the explosives under test. Our model predicts well across a wide range of explosive types, spanning a broad range of explosive performance and sensitivity. We find that properties related to explosive performance, such as heat of explosion, oxygen balance, and functional group, are highly predictive of explosive handling sensitivity. Yet, models that omit many of these properties still perform well. Our results suggest that there is not one or even several factors that explain explosive handling sensitivity, but that there are many complex, interrelated effects at play.